These studies are designed to provide preclinical information for the development of medications to be used in the treatment of drug abuse. The primary focus of this work is to determine pharmacological means for modulating behavioral and toxic actions of abused compounds, and to evaluate new chemical entities (synthesized in house and from outside sources) for safety and efficacy in the design of potential rational treatment strategies. The primary findings and implications for the current year are: (1) Certain sigma-receptor ligands have shown an ability to antagonize some of the pharmacological effects of cocaine. We are examining other sigma ligands to determine which ones are most effective as antagonists of cocaine and to determine the mechanisms of this effect. Ongoing studies will determine whether other behavioral effects of cocaine related to its abuse and toxicity can be similarly altered. (2) A variety of compounds proposed by NIDA as potential treatments for cocaine abuse are being examined in preclinical screens for safety and efficacy as potential treatments for cocaine abuse. (3) Studies have indicated that the locomotor stimulant effects of cocaine can be modulated by several excitatory amino acid antagonists. These drugs are being characterized and various other effects of cocaine, such as the toxic, subjective and reinforcing effects, will be examined as indicated as further results unfold. (4) Studies of the lethal effects of cocaine have indicated a significant peripheral D1 component to the mediation of these effects. We have synthesized several peripherally active D1 antagonists and will be testing them for their effectiveness in protecting against the lethal effects of cocaine. (5) The synthetic chemistry component of the laboratory is developing novel compounds as potential treatments against cocaine abuse.